A CMOS Imager for DNA Detection
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A CMOS Imager for DNA Detection
Samir Parikh
MASc Thesis Defense
Dept. of Electrical and Computer Engineering
University of Toronto
24th January, 2007
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Outline
Introduction Motivation and Objectives Design Details Experimental Results Conclusion Future Work
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Introduction: DNA Microarrays
ssDNA FragmentsDNA
Chemical Processing
DNA microarrays used to detect DNA sequence concentration
DNA is split into its two constituent strands One strand is broken into fragments
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Introduction: Using DNA Microarrays
Within a spot multiple identical ssDNA probes are attached Each spot is tailored to match with a particular target ssDNA
sequence target ssDNA is created from Messenger RNA extracted from a cell
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Introduction: DNA Detection
Solution containing target ssDNA+fluorescing dye molecule is introduced to the slide
Spots on the DNA microarray pair/unpair depending on the nucleotide sequence of the probe and target ssDNA
DNA microarray is washed to remove unpaired target ssDNA
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Introduction: DNA Detection
Solution containing target ssDNA+fluorescing dye molecule is introduced to the slide
Spots on the DNA microarray pair/unpair depending on the nucleotide sequence of the probe and target ssDNA
DNA microarray is washed to remove unpaired target ssDNA
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Introduction: Basic Microarray Scanner
Fluorescing dye molecule absorbs energy at λ1nm and emits energy at λ2nm
Light detectors are discussed in the next slide
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Introduction: Existing Light Detectors
Detector Disadvantages
PMT
Bulky Expensive PCB-level integration 10μm resolution → Long scan time
CCD Needs to be cooled Monolithic integration is costly
Commonly used detectors in microarray scanners are: Photomultiplier Tube (PMT) - accurate Charge-Coupled Device (CCD) - fast
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Motivation and Objectives
Determine the feasibility of using standard CMOS technology for light detection and quantification Integrated Smaller Cheaper
Validate the design without the use of cooling Reduce cost related to cooling Reduce power consumption due to cooling equip.
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Design Details: Microarray Scanner
Signal from entire spot captured at once
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Design Details: Microarray Scanner
Signal from entire spot captured at once
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Design Details: Microarray Scanner
Signal from entire spot captured at once
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Design Details: Microarray Scanner
Signal from entire spot captured at once
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Design Details: Microarray Scanner
Signal from entire spot captured at once
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Design Details: Active Pixel Sensor (APS)
photons
5-transistor circuit with pseudo-differential output Pinned photodiode performs the photon-to-electron conversion Circuits has two phases: reset and integration
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Design Details: ΔΣ Modulator
2nd Order Discrete-Time ΔΣ Can be combined with a decimation
filter for a complete ADC Boser-Wooley Architecture Delaying Integrators with 1bit feedback Folded-Cascode Op-amp used
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Design Details: Fabricated Chip
TSMC 1P6M
0.18µm CMOS
Core Area
690×490 μm2
Die Area
1.2×1.4 mm2
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Experimental Results: APS
Photodetector Type P+/n-well/Psubstrate
Sensitivity to low light < 2.6 х 10-2 lux
SNR @ 2.6 х 10-2 lux 16.6dB
Dark-signal@(room temp.) 10mV/sec
Source-Follower non-linearity 0.12%
Photodetector Size 150µm х 150µm
Pixel Size 162.5µm х 154µm
Fill Rate 90%
Dark signal limits the integration time for the APS Low light sensitivity sets the min # of photons detectable
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Experimental Results: ΔΣ Modulator
Simulation includes flicker and thermal noise Close matching between simulation and measured
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Experimental Results: ΔΣ ModulatorDiscrete-Time 2nd Order Single-bit ΔΣ
Power Consumption 26.4 mW
Peak SNDR 75.9 dB
Effective Number of Bits 12 bits
Dynamic Range 74.63 dB
SFDR 85.5 dB
Sampling Rate 3.6 MHz
Nyquist Sampling Rate 14.2 kHz
Commercial microarray scanners have 12 to 16-bits accuracy Sampling rate sets an upper limit on the maximum light level Sampling rate not critical, minimum light level is more important
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Experimental Results: Microarray Scanner Setup
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Experimental Results: Microarray Scanner Setup
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Experimental Results: Microarray Scanner Setup
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Experimental Results: Microarray Scanner Setup
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Experimental Results: Scanner Characterization Slide
Slide contains spots with dilution series Each spot contains fluorescing dye molecules with fixed density Spot density (fluorophores/um2) decreases at a fixed rate
Decreasing dye density
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Experimental Results: Microarray Scanner
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Experimental Results: Commercial Microarray Scanner
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Discussion: Microarray Scanner Portability Potential
Microarray scanner: Smaller, integrated detector w/o cooling Agilent scanner: PMT
Detection Limit Microarray scanner: 4590 fluorophores/um2
Agilent scanner: 4 fluorophores/um2
Resolution and Scan time Microarray scanner: Larger pixel→Entire spot imaged at once Agilent scanner: 10μm resolution→takes longer to image a spot Microarray scanner: Multiple pixels → short scan time Agilent scanner: Single element → long scan time (8 min/slide)
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Discussion: APS
Dark signal of APS not the limiting factor Background of the slide = 1.5 ADU/sample Dark signal of the APS = 0.08 ADU/sample Integration time of the APS is limited by the slide background
Improve the sensitivity of the APS beyond 2.6х10-2 lux Increase its conversion gain Reduce its read noise and reset noise
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Discussion: Optical and Mechanical
Improve optical coupling between
APS ↔ fluorescing spots Use a focusing/collimating element Compensate for slide tilt
Reduce laser noise and drift from 3% to 0.1% Improved power supply Better laser control/feedback
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Conclusion
Standard CMOS technology shows potential to be an alternative to existing PMT/CCD detectors used in microarray scanners
The detection limit of a microarray scanner is determined by: Mechanical and Optical Non-idealities Detector Non-idealities
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Future Work
Improve the conversion gain of the APS Reduce the read noise, and reset noise of the
APS Improve the accuracy of the ADC
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Thank You
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